Pro-inflammatory complement activation by the Aβ peptide of Alzheimer’s disease is biologically significant and can be blocked by vaccinia virus complement control protein

The amyloid plaque is the hallmark of Alzheimer’s disease (AD). The transmembrane domain and a portion of the C-terminus (Aβ) of the amyloid precursor protein, are known to form the nucleus of the amyloid plaque. It has been demonstrated recently, using in vitro assays, that the Aβ peptide can activate both the classical (antibody-independent) and alternate pathways of complement activation. The proposed complement activation is due to the binding of Aβ to the complement components Clq and C3, respectively, which initiate formation of the proinflammatory C5a and C5b-9 membrane attack complex. In this report, we have investigated the in vitro findings for the likely complement-dependent proinflammatory properties of the Alzheimer’s disease Aβ peptide. We have performed experiments using congenic C5-deficient and C5-sufficient mice injected with synthetic Aβ and recombinant polypeptide (C-100) containing Aβ. Injection of C-100 into C5-sufficient mice induced a clear increase in the number of polymorphonuclear cells (neutrophils) at the site of injection due to complement activation and the subsequent release of proinflammatory chemtoactic factors. In sharp contrast, the C5-deficient mice did not show any increase in cellular influx. The vaccinia virus complement control protein, an inhibitor of both the classical and alternate pathway can down-regulate the biologically significant activation of complement by Aβ, as demonstrated by an in vitro immunassay. The therapeutic down-regulation of Aβ-caused complement activation could greatly alleviate the progression of some of the chronic neurodegeneration characteristic of Alzheimer’s disease.